1-hydroxy-4-methoxy-7-keto-13-methyl-5, 6, 7, 9, 10, 13-hexahydrophenanthrene and processes of preparing the same



United States Patent William F. Newhall, Winter Haven, Fla., assignor toMerck & Co., Inc., Railway, N. J., a corporation of New Jersey NoDrawing. Application August 24, 1954,

, Serial No. 451,957

4 Claims. (Cl. 260 590) This invention is concerned generally with novelcompounds valuable as intermediates in the total synthesis of steriods,and potentially useful in the synthetic preparation of steroid hormonessuch as 11-dehydro-l7-hydroxycorticosterone, commonly known ascortisone. More particularly, this invention relates to the novelcompound 1 hydroxy 4 methoxy 7 keto l3 methyl5,6,7,9,10,13-hexahydrophenanthrene, to the process of preparing thiscompound, and to the novel intermediate compounds utilized in thisprocess. This 1-hydroxyl-4- methoxy 7 keto 13 methyl 5,6,7,9,l0,13hexahydrophenanthrene is of value as an intermediate in the totalsynthesis of steroids and, alternatively, is useful as an intermediatein the synthesis of compounds useful as antitussives.

This application is a continuation-in-part of my copending applicationSerial No. 193,291, filed October 31, 1950, now abandoned.

The compound 1-hydroxy-4-methoxy-7-keto-13-methyl-5,6,7,9,l0,13-hexahydrophenanthrene can be represented by the followingstructural formula:

I have discovered that this compound can be prepared according to anovel synthetic procedure which is conducted as follows: hydroquinonedimethyl ether (compound 1 on thefollowing page) is reacted Withsuccinic anhydride in the presence of aluminum chloride to producefl-(Z-hydroxy-S-methoxy-benzoyl)-propionic acid (compound 2), whichcompound is then reduced to formgamma-(Z-hydroxy-S-methoxy-phenyl)-butyric acid (compound 3). The lattercompound is heated with an aqueous solution of mineral acid therebyforming S-hydroxy- 8-methoxy-tetralone-1 (compound 4), which is thenreacted with methyl magnesium iodide to producel-hydroxy-4-methoxy-5-methyl-7,8-dihydronaphthalene (compound 5). Thisproduct is reacted with osmium tetroxide in an organic solvent solutionand the intermediate osmate ester thus formed is hydrolyzed therebyforming 1,5,6- trihydroxy- 4 -methoxy 5 methyl 5,6,7,8tetrahydronaphthalene (compound 6) which is heated with an aqueousmineral acid solution to form 5 hydroxy-8- methoxy-l-methyl'tetralone-2(compound 7); The 5- hydroxy-8-methoxy-l-methyl-tetralone-2 is thencondensed with diethylamino butanoue-Z-methiodide in the presence of analkaline condensing agent thereby forming 1 hydroxy 4 methoxy 7 keto 13methyl 5,6,7 ,9, 10,13-hexahydrophenanthrene (compound 8).

2,720,542 Patented Oct. 11, 1955 lows:

O C H3 0 CHa Succinic anhydride Aluminum chloride O GENE) O OH 0 CH3 HCompound 1 Reductiop/ Compound 2 j i O CH:

O C Hz O I i ll Aqueous sulfuric acid CHzCHzCH2COOH Heat I i OH OHCompound 3 ggig g Compound 4 0 on; O CHa 0 Ha CH3 I O H i i (l) Osmiumtetroxide OH V (2) Hydrolysis n OH Compound 5 g iy Compound 6 O CH: 0

H3 0 CH3 1 out o Diethylamino butanonea methiodide Alkaline condensingagent Compound 7 Compound 8 The reaction between the hydroquinonedimethyl ether (compound 1) and the succinic anhydride is carried out bybringing the reactants together in an organic solvent such as'nitrobenzene, carbon disulfide, tetrachloroethane, and the like, in thepresence of aluminum chloride, and heating theresulting mixture at atemperature within the range of 55-60 C. for a period of approximately 2to 3 hours. The preferred solvent for this reaction is nitrobenzene. Ihave found that the temperature and the time of reaction are criticalfactors in this step. In particular, it is essential to conduct thereaction at a temperature within the range of 55-60 C since, at higheror lower temperatures, various side reac The reaction is convenientlycarried out by dissolving equimolecular quantities of hydroquinonedimethyl ether and succinic anhydride in nitrobenzene, cooling thismixture to approximately 10 C. and adding approximately 2 molecularequivalents of anhydrous aluminum chloride These reactions may bechemically represented as folto this mixture with cooling. During theaddition, the temperature should-not be allowed to rise aboveapproximately 35 C. After the addition of aluminum chloride is complete,the resulting solution of the reactants is warmed slowly to atemperature between approximately 55 and 60 C. and the solution ismaintained at this temperature, with stirring, for about 3 hours. Thefi-(Z- hydroxy--methoxy-benzoyl)-propionic acid thus produced isrecovered from the dark viscous reaction mixture by pouring said mixtureinto excess aqueous acid solution with cooling. The nitrobenzene is thenseparated from the resulting mixture, and the desired product isconveniently recovered from the residue, in crystalline form byextraction with an organic solvent such as benzene. It is convenientlypurified by recrystallization from an aqueous organic solvent such asaqueous methanol.

The reduction of fl-(2-hydroxy-5-methoxy-benzoyl) propionic acid toproduce gamma-(2-hydroxy-5- methoxyphenyl) -butyric acid (compound 3) ispreferably carried out reacting said p-(2-hydroxy-S-methoxy-benzoyl)-propionic acid in aqueous solution containing one equivalent ofpotassium hydroxide with hydrogen at high pressure in the presence of acopper chromium oxide catalyst. The hydrogenation reaction is bestconducted at a temperature within the range 140180 C. The foregoinghydrogenation procedure possesses the advantage over other methods ofreduction that the carbonyl group of the starting material is convertedin good yield directly, in a single reaction step, to the correspondingmethylene substituent. Other methods of catalytic hydrogenation may beemployed, however, if desired, as for example a two-step hydrogenationreaction in which the S-(Z-hyd'roxy-5-methoxy-benzoyl)-propionic acid inaqueous alkaline solution is reacted with hydrogen in the presence ofRaney nickel catalyst and the intermediate product is then dissolved inmethanol and the solution reacted with hydrogen in contact with apalladium catalyst. This method is not as satisfactory, however, as thehydrogenation utilizing copper chromium oxide catalyst.

In carrying out my preferred method of reduction, the/3-(2-hydroxy-5-methoxy-benzoyl)-propionic acid is dissolved in anaqueous alkaline solution containing one equivalent of potassiumhydroxide, approximately by weight of copper chromium oxide catalyst isadded to the solution, and the resulting mixture is heated and shaken incontact with hydrogen at high pressure, preferably at about 3500 poundsper square inch. The hydrogenation reaction is conveniently carried outby heating and shaking the reaction mixture for approximately 2 hours ata temperature of 160 0., followed by an additional heating period ofseveral hours at a temperature of about 180 C. The gamma-(Lhydroxy-S-methoxy-phenyD-butyric acid thus formed is recovered from the aqueousreaction mixture by conventional means, as for example by filtering thecatalyst, acidifying the filtrate and extracting the gamma(2-hydroxy-5-methoxyphenyl)-butyric acid with ether. The product is thenrecovered from the ether solution by evaporating the ether and isconveniently purified by distillation in vacuo.

The gamma (2 hydroxy 5 methoxy phenyl) butyric. acid is then heated withaqueous sulfuric acid thereby producing 5-hydroxy-8-methoxy-tetralone-l(compound 4). .It is ordinarily preferred to utilize 85% sulfuric acid.It has been found that the reaction can be brought to substantialcompletion by heating the aqueous acidic reaction mixture for a periodof about 1 hour at approximately 80100 C. The5-hydroxy-8-methoxytetralone-l is conveniently recovered from thereaction solution by diluting it with water. When the solution is cooledthe product crystallizes therefrom and can be recovered by filtration.The S-hydroxy-8-methoxy-tetralone-1 is very sparingly soluble in benzeneor ether and extremely soluble in inethanoll It is conveniently purifiedbyrecrystallization from aqueous methanol.

The Grignard reaction between the 5-hydroxy-8-meth- 4 oxy-tetralone-land methyl magnesium iodide is carried out utilizing, as a solvent forthe reaction, a mixture of diethyl ether and pyridine. It is essentialthat the Grignard reaction be conducted in a solvent comprising pyridinein view of the fact that the tetralone is nearly insoluble inconventional solvents employed in Grignard reactions such as ether,benzene and dioxane. Moreover, it was found that the order of additionof the reactants is critical. For example, when a pyridine solution ofthe S-hydroxy-8-methoxy-tetralone-1 was added to an ether solution ofmethyl magnesium iodide, it was found that considerable amounts (30-40%of unreact'ed 1 tetralone are recovered from the reaction solution andalent of 5-hydroxy-8'-methoxy-tetralone-1.

and mineral acid.

during the reaction, the reaction mixture being more of a suspensionthan a solution. Pyridine appears to be essential to this Grignardreaction because of its. ability to dissolve both the tetralone startingmaterial as Well as; the initially-formed complex of5-hydroxy-8-methoxytetralone-l with the Grignard reagent.

The mixture of the reactants is then stirred at room te perature forapproximately 18 hours to insure completion of the reaction and theGrignard complex is decomposed by pouring the reaction solution into amixture of lee, h r s n fd hY QXY' methoxy 5 methyl 5,6,7,8tetrahydronaphthalene thus formed is extracted from the aqueous acidmixture. by means of an organic solvent such as ether. The evaporationof the ether and distillation of the residual material in vacuo resultsin the dehydration of the tertiary alcohol intermediate to form thecorresponding olefin, 1 hydroxy 4 methoxy 5 methyl7-,8-dihydronaphthalene (compound 5). This product can be further.purified if desired by recrystallization from an organic solvent such ashexane.

The reaction between 1 hydroxy 4 methoxy 5 methyl-7,8-dihydronaphthaleneand osmium tetroxide is conveniently carried out by adding osmiumtetroxide to a solution of the dihydronaphthalcne compound in ananhydrous organic solvent, such as anhydrous diethyl room temperature,preferably for a period of aPProxiether or benzene, whereupon immediateseparation of the intermediate 5,6-osmic ester of 1,5,6-trihydroxy-4-methoxy 5 methyl 5,6,7,8 tetrahydronaphthalene occurs. The reactionmixture is then allowed to stand at mately 7 to. 8 hours, at which timethe separation of the osmic ester is substantially complete. Althoughthe reaction mixture may be treated without purification to. accomplishhydrolysis of the osmate ester, it is preferable to collect theintermediate osmate ester on a filter and to thoroughly wash it with anorganic solvent such as diethyl ether to..remove impurities. Thepurified 5,6- osmate ester of 1,5,6 trihydroxy 4 methoxy-Sr-methyl- 5,6,7,8-tetrahydronaphthalene is then hydrolyzed by heat-. ing with anaqueous hydrochloric acid solution or an aqueous solution of sodiumsulfite to produce an aqueous reaction mixture containing1,5,6-trihydroxy-'4-methoxy- 5 methyl 5,6,7,8 tetrahydronaphthalene(compound 6). This compound is conveniently recovered from the.

reaction mixture by filtering thereby removing the pre-.

cipitate of reduced osmium compounds and undissolvedv sodium sulfite,evaporating the aqueous solution .to ap-.

proximately its volume, adjusting the solution to.v

neutralityby the addition of mineral acid, and extractingthe productfrom the neutral aqeuous solution utilizing.

an organic. solvent such as diethyl ether. Uponevaporm tion of thecombined ether extracts there is obtained substantially pure 1,5,6trihydroxy 4 methoxy pound 7) is accomplished by heating said 1,5,6 trihydroxy 4 methoxy 5 methyl 5,6,7,8 tetrahy dronaphthalene with anaqueous mineral acid solution, preferably with an aqeuous ethanolicsolution of sulfuric acid. When the preferred reaction conditions,wherein the 1,5,6 trihydroxy 4 methoxy 5 methyl 5,6,7,8tetrahydronaphthalene is suspended in an aqueous ethanolic solution ofsulfuric acid are utilized, it has been found that the conversion can beeffected by heating the mixture under reflux for a period of about 1%hours. When such a reaction solution is cooled the desired productcrystallizes therefrom and can be recovered by filtration to produce asubstantially quantitative yield of said 5 hydroxy 8 methoxy 1 methyltetralone 2. If desired, this compound can be readily purified byrecrystallization from 50% aqueous alcohol.

The reaction between the 5 hydroxy 8 methoxy 1 methyl tetralone 2 andthe diethylamino bntanone Z-methiodide is carried out in an anhydrousorganic solvent solution containing an alkaline condensing agent.Suitable alkaline condensing agents are alkali metal alkoxides, such aspotassium methoxide, potassium ethoxide, sodium methoxide, sodiumethoxide, and alkali metal amides, such as sodium amide, potassiumamide, and the like. When alkali metal alkoxides are used, the organicsolvent used as a reaction medium is a lower aliphatic alcohol, such asmethanol, ethanol, and the like; when alkali metal amides are used, theorganic solvent employed is benzene, toluene, or xylene.

The diethylamino-butanone-2-methiodide is convenient- 1y prepared byadding methyl iodide to diethylaminobutanone-2 while subjecting thereaction mixture to cooling, whereby the desireddiethylamino-butanone-2- methiodide is produced in crystalline form. Asolution of 5 hydroxy- 8 methoxy 1 -methyl tetralone 2 in the solventselected for the reaction is then added to thediethylamino-butanone-2-methiodide, followed by a solution of thealkaline condensing agent in the reaction solvent. The mixture isallowed to stand at a temperature of 0-5 C. for approximately one andone-half hours. and is then heated under refluex for an additionalperiod of approximately one-half hour.

The 1 hydroxy 4 methoxy 7 keto 13 methyl 5,6,7,9,10,13hexahydrophenanthrene thus formed is re covered from the reactionmixture by acidifying said mixture with an excess of mineral acid andextracting the acidified aqueous solution with an organic solvent suchas ether. The product contained in the ether solution is thentransferred back to the aqueous phase by extracting the ether solutionwith an aqueous alkaline solution, preferably 2.5 N aqueous sodiumhydroxide. Upon acidification of the alkaline extract, the desiredproduct separates as an oil which can be crystallized from an aqeuousalcoholic solution to produce substantially pure 1 hydroxy 4 methoxy 7keto 13 methyl 5,6,7,9,10,13 hexahydrophenanthrene (compound 8).

The. latter compound can be converted to 1-keto-4- methoxy 7 hydroxy 13methylperhydrophenanthrene as follows: The 1 hydroxy 4 methoxy 7 keto13- methyl 5,6,7,9,10,13 hexahydrophenanthrene is reduced in thepresence of a catalyst to form 1,7-dihydroxy-4- methoxy 13 methyl5,6,7,8,9,10,l3,l4 octahydrophenanthrene, which compound is then treatedwith acetic anhydride in the presence of acetic acid in order to convertit into 1 hydroxy 4 methoxy 7 acetoxy l3- methyl 5,6,7,8,9,10,13,14octahydrophenanthrene. This latter compound is hydrogenated inmethylcyclohexane solution in the presence of palladium-strontiumcarbonate catalyst thereby forming 1 hydroxy 4 methoxy- 7 acetoxy 13methylperhydrophenanthrene which is oxidized to form 1 keto 4 methoxy 7acetoxy 13- methylperhydrophenanthrene, and the latter treated withalcoholic potassium hydroxide to produce 1 keto 4- methoxy 7 hydroxy 13methylperhydrophenanthrene. This latter compound, in addition to beinguseful in the total synthesis of steroids, can be treated withmethylamine and the reaction product reduced by known methods to form 1(N methylamino) 4 methoxy 7- hydroxy l3 inethylperhyclrophenanthrene,which compound possesses antitussive activity.

The following examples illustrate methods of carrying out the presentinvention, but it is to be understood that these examples are given forpurposes of illustration and not of limitation.

Example 1 320 gms. (2.32 moles) of hydroquinone dimethyl ether, 240gins. (2.40 moles) of succinic anhydride and 2 liters of nitrobenzenewere placed in a 5 liter round-bottomed flask, and the mixture wascooled to 10 C. 640 gms. (4.81 moles) of anhydrous aluminum chloridewere added to the cooled mixture in small portions over a period ofabout 1 hour. During the addition of the aluminum chloride the contentsof the flask were stirred vigorously and the flask and its contents werecooled by immersion in an ice bath. At no time was the temperature ofthe reaction mixture allowed to rise above 35 C. After the addition ofthe aluminum chloride was complete, the resulting solution was warmedslowly to 60 C., and this temperature was maintained with stirring forapproximately 3 hours. The reaction solution was then cooled to 35 C.,and the resulting dark viscous solution was poured onto a mixture of 400ml. of concentrated hydrochloric acid and 700 g. of ice. Thenitrobenzene was removed irom the resulting aqueous mixture by steamdistillation, and the residue was then cooled to 10 C., whereupon crude,8 (2 hydroxy 5 methoxybenzoyl) propionic acid crystallized from themixture. The crystalline material was recovered by filtration utilizinga suction filter. The product was sucked as dry as possible on thefilter, was dissolved in 6 liters of benzene and the benzene solutionwas then heated under reflux for approximately 2 hours. The benzenesolution of the product was decanted and cooled to 5 C. to aidcrystallization, whereupon the product crystallized as green prismswhich were recovered by filtration and dried to give 335 gms. ofpartially-purified ,8 (2 hydroxy 5 methoxy benzoyl): propionic acid; M.P. 128135 C.; yield approximately 62% of theory. This material wasfurther purified by recrystallization from a 50-50 mixture of methanoland Water (including treatment of the methanolic solution thereof withactivated charcoal (Darco)) to afford 275 gms. of substantially pure ,8(2 hydroxy 5 methoxybenzoyD-propionic acid; M. P. 137-142 C.; yieldapproximately 51% of theory. The 8 (2 hydroxy 5methoxy-benzoyl)-propionic acid thus obtained was soluble in dilutesodium carbonate solution and is reprecipitated unchanged from thissolution by the addition of acid thereto. It gives a positive ferricchloride test (blue green).

Example 2 A mixture of 400 gms. (1.8 moles) of B (2 hydroxy- 5methoxybenzoyl) propionic acid, 1 liter of 1.8 N aqueous potassiumhydroxide and 50 gms. of copper chromium oxide was heated and shaken incontact with hydrogen at a pressure of 3500 p. s. i. (pounds per squareinch). The hydrogenation was carried out: for a period of 2 hours whilemaintaining the temperature of the reactants at C. The temperature ofthe reaction mixture was then raised to C. and the mixture wasmaintained at that temperature for a period of several hours time whilecontinuing the shaking of the mixture under a hydrogenation pressure of3500 p. s. i. The reaction mixture was then filtered to remove thecatalyst, the filtrate was acidified with aqueous hydrochloric acid to apH of 2, and the. resulting mixture was then extracted with ether. Theether extract was washed with a saturated aqueous solution of sodiumchloride and dried over sodium sulfate. The dried ether solution wasthen evaporated to produce a residual oil, and this oil was subjected tovacuum distillation to give 270 gms. of gamma-(Z-hydroxy 5methoxyphenyl) butyric acid which was obtained in the form ofa heavyoil; B. P. 170-178 C./0.1 mm. Yield: 71% of theory. This product, asobtained by distillation, is sufficiently pure to use directly for thepreparation of S-hydroxy-S-methoxy-tetralone-1 as de scribed in Example3 hereinbelow.

This oil can be further purified if desired by crystallization frompetroleum ether (B. P. 6080 C.). A sample of this oil was recrystallizedseveral times from petroleum ether to give white prisms of substantiallypure gamma-(2- hyfdroxy-S-methoxyphenyl)-butyric acid; M. P. 6869.

Example 3 260 gms. (1.24 moles) ofgamma-(Z-hydroxy-S-methoxyphehyD-butyric acid were dissolved in 300 ml.of water containing 940 ml. of concentrated sulfuric acid, and theresulting solution was heated at 98 C. for a period of approximately 1hour. The dark reaction solution was poured into 8 liters of ice water,and the mixture was cooled to C. and allowed to stand at thattemperature for a period of approximately 15 hours. The tan crystallineproduct which precipitated was recovered by filtration, washedthoroughly with cold water, and dissolved in an aqueous methanolsolution containing 700 ml. of methanol and 2 liters of water. Thismethanolic solution was then treated with activated charcoal (Darco G60), filtered hot, and the filtrate allowed to cool, whereupon theproduct crystallized in the form of yellow platelets which wererecovered by filtration and dried to produce 200 gms. of5-hydr0xy-8-methoxytetralone-1; M. P. 155-160 C.; yield approximately82% of theory. This material was further purified by recrystallizationfrom aqueous methanol to give 170 gms. of substantially pure5-hydroxy-8-methoxy-tetralone-1 which was obtained in the form of lightyellow plates; M. P. 167170 C.; yield approximately 68% of theory.Analysis.- Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.67; H,5.99.

- Example 4 78 ml. (1.25 moles) of methyl iodide was slowly added,with'stirring, to 30 gins. (1.25 moles) of magnesium, suspended in 300ml. of dry ether, to produce an ethereal solution of methyl magnesiumiodide. 300 ml of this solution was added to a cold solution of 48 gms.(0.25 mole) of 5-hydroxy-8-methoxytetralone-1 in 400 ml. of drypyridine. After the addition of the methyl magnesium iodide solution wascompleted, 750 ml. of dry ether was added to the reaction mixture tofacilitate stirring of the solid Grignard complex. The resulting mixturewas stirred at room temperature for approximately 18 hours, and thecomplex was then decomposed by pouring the etheral reaction mixture intoa mixture of ice and 500 ml. of aqueous hydrochloric acid. The resultingaqueous mixture was then saturated with sodium chloride and the aqueousphase was extracted four times with ether. The combined ether extractswere washed with aqueous sodium carbonate solution, then with water anddried over anhydrous sodium sulfate. The dried ether solution wasevaporated to give 38 guts. of crystalline solid which was subjected tovacuum distillation at a temperature of 115-130 C. at a pressure of lessthan 0.1 mm. to give 34 gms. of1-hydroxy4-methoxy-5-methyl-7,8-dihydronaphthalene which was obtained inthe form of a crystalline so id; M. P. 8084 C.; yield approximately 72%of theory. This product was recrystallized from hexane (B. P. 90-100"C.) to produce 32 gms. of substantially pure 1 hydroxy 4 methoxy 5methyl 7,8 dihydronaphthalene; M. P-. 8 5.86 C. Analysis..Calcd for75.68; H, 7.22; CH3O, 15.17.

Example 5 A solution of 7.266 gms. (0.0286 mole) of osmium tetraoxide inml. of dry diethyl ether was added to a solution of 4.9 gms. (0.0257mole) of 1-hydroxy-4- methoxy-Smethyl-7,8-dihydronaphthalene in 50 ml.of dry diethyl ether. An immediate separation of thedark brown osmicester of1,5,6-trihydroxy-4-methoxy-S-methyl-5,6,7,8-tetrahydronaphthaleneoccurred along with a definite evolution of-heat. The mixture wasallowed to stand at room temperature for a period of approximately 18hours, and the solid osmic ester of 1,5,6-trihydroxy-4- methoxy-S-1nethyl-5 ,6,7,8 tetrahydronaphthalene was then recovered from themixture by filtration. The osmic ester was then dissolved in 250 ml. ofethanol, a solution of 29 guts. of sodium sulfite in 250 ml. of waterwas added to the ethanolic solution, andthe resulting mixture was heatedunder reflux for a period of approximately two hours. The precipitate ofreducedo srnium compound together with undissolved sodium sulfite wasseparated from the reaction mixture by filtration through diatomaceoussilica (Supercel). The filter cake was washed with several portions ofhot ethanol andhot water and the combined filtrates were evaporated invacuo to a volume of about 250 'ml. The residual solution was madeneutral (pH 7) by the addition of 2.5 N hydrochloric acid, and theresulting aqueous solution was extracted with five portions of diethylether. The ether extracts were combined and the resulting ether solutionwas partially dried with anhydrous sodium sulfate. The ether solutionwas then evaporated in vacuum to produce a crystalline residue which wasthen recrystallized from 20 ml. of chloroform by the addition thereto of5 ml. of petroleum ether; (B. P. 3060 C.) thereby giving 4 grns. ofpartially purified 1,5,6 trihydroxy- 4 methoxy 5 methyl5,6,7,8-tetrahydronaphthalene; M. P. 133-135" C.; yield approximately64% of theory.

A sample of this material was further purified bycrystallization fromchloroform'by the addition of petroleum ether to give substantially pure1,5,6-trihyd-roXy-4-meth-- oxy-S-methyl 5,6,7,8'-tetrahydronaphthalene;M. P. 147- 148 C., with softening at C. Analysis.-Calcd for CHI-116041C, 64.27; H, 7.19; CH30, 13.84. Found: C, 64.53; H. 6.91; CH3O-, 14.48.

Example 6.

0.2 gm. of '1,5',6-trihydroxy-4-methoxy-5-methyl-5,6,7, 8-tetrahydronaphthalene (M. P. 135-136 C.) was suspended in 1 ml. of waterand 1 ml. of ethanol containing 8 drops of concentrated sulfuric acid.The resulting mixture was heated underreflux for 1 /2 hours. 1 ml. ofwater was added to the reaction solution and the resulting mixture wascooled in an ice bath. The crystalline product which separated wasrecovered by filtration and Example 7 715 mgs. (0.005 mole) ofdiethylaminobutauone-Z was swirled in a small flask and cooled in icewhile adding thereto 710 mg. (0.005 mole) of methyl iodide. Thecrystalline diethylamino-butanone-Z-methiodide formed on the walls ofthe flask. When no more liquid remained, the flask was kept in ice for30 minutes and was then placed on a water bath for a period ofapproximately 45 minutes. A solution of 1 gm. (0.005 mole) of 5-hydroxy-S-methoxy-l-mefl1yltetralone-2 in ml. of dry ethanol was added to theflask containing the methiodide. Dry nitrogen was introduced into theflask to expel the air, and a solution of potassium ethylate (preparedby reacting 432 mg. (0.01 mole) of potassium with 10 ml. of dry ethanol)was then added to the mixture contained in the flask. The contents ofthe flask were then swirled and cooled for a period of 30 minutes andthe flask was then immersed in an ice bath for a period of 1 hour. Thereaction solution in the flask was then boiled gently for a period of 25minutes, and an excess of 2 N sulfuric acid was then added to thereaction solution. The acidified aqueous reaction mixture was extractedwith ether and the resulting ether extract was extracted with an aqueoussolution of 2.5 N aqueous sodium hydroxide. The aqueous alkaline extractwas then acidified, whereupon 1 gm. of an oil separated. This oil wasdissolved in an aqueous methanol solution, the solution was treated withactivated charcoal (Darco G60) and filtered, and the filtrate wasallowed to stand whereupon the product crystallized and was recovered byfiltration. The solid crystalline product was sublimed and was thenrecrystallized twice from methanol to produce substantially pure1-hydroxy-4- methoxy 7 keto 13 methyl 5,6,7,9,10,13hexahydrophenanthrene which was obtained in the form of pale yellowprisms; M. P. 178180 C. Analysis.- Calcd for C16H1803I C, 74.39; H,7.02; CHsO-, 12.01. Found: C, 73.85; H, 7.01; CH3O-, 12.83.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of my invention.

I claim:

1. The process of preparing 1-hydroxy4-rnethoXy-7- keto 13 methyl5,6,19,10,13 hexahydrophenanthrene which comprises reacting hydroquinonedimethyl ether with succinic anhydride in the presence of aluminumchloride, intimately contacting the reaction mixture with an aqueousacid solution and reducing the resulting [3-(Z-hydroxy-S-methoxy-benzoyl)-propionic acid to producegamma(Z-hydroxy-S-methoxy-phenyl) -butyric acid, heating the lattercompound with an aqueous solution of sulfuric acid to form5-hydroxy-S-rnethoxy-tetralone-1, reacting said5-hydroxy-S-methoxy-tetralone-l with methyl magnesium iodide followed byhydrolysis of the Grignard intermediate thus obtained to form1-hydroxy-4-methoxy- 5-methyl-7,S-dihydronaphthalene, reacting thelatter compound with osmium tetroxide in organic solvent solution andhydrolyzing the intermediate osmate ester thus formed to produce1,5,6-trihydroxy-4-methoxy-5-methyl-5,6,7,8- tetrahydronaphthalene,heating this compound with an aqueous mineral acid solution to formS-hydroxy-S- methoxy-l-methyl-tetralone-Z, and reacting saidS-hydroxy-S-methoxy-l-methyl-tetralone-2 withdiethylaminobutanone-2-methiodide in the presence of an alkalinecondensing agent.

2. The process of preparing 1-hydroxy-4-methoxy-7- keto 13 methyl5,6,7,9,10,13 hexahydrophenanthrene which comprises reacting5-hydroxy-8-methoxy-1- methyl-tetralone-Z with diethylaminobutanone-Zmethiodide, said reaction being carried out by heating the reactantstogether in an anhydrous organic solvent solution in the presence of analkaline condensing: agent.

3. The process of preparing l-hydroxy-4-meth0Xy-7- keto 13 methyl5,6,7,9,l0,13 hexahydrophenanthrene which comprises reactingS-hydroxy-S-methoxy-lmethyl-tetralone-2 withdiethylaminobutanone-Z-methiodide, said reaction being carried out byheating the reactants together in the presence of a substantiallyanhydrous ethanolic solution of potassium ethoxide.

4. l-hydroxy 4 methoxy 7 keto 13 methyl-5,6,7,9,10,l3-hexadrophenanthrene.

No references cited.

1. THE PROCESS OF PREPARING 1-HYDROXY-4-METHOXY-7KETO - 13 - METHYL -5,6,7,9,10,13 - HEXAHYDROPHENANTHRENE WHICH COMPRISES REACTINGHYDROQUINONE DIMETHYL ETHER WITH SUCCINIC ANHYDRIDE IN THE PRESENCE OFALUMINUM CHLORIDE, INTIMATELY CONTACTING THE REACTION MIXTURE WITH ANAQUEOUS ACID SOLUTION AND REDUCING THE RESULTINGB(2-HYDROXY-5-METHOXY-BENZOYL)-PROOPIONIC ACID TO PRODUCEGAMMA-(2-HYDROXY-5-METHOXY-PHENYL)BUTYRIC ACID, HEATING THE LATTERCOMPOUND WITH AN AQUEOUS SOLUTION F SULFURIC ACID TO FORM5-HYDROXY-8-METHOXY-TETRALONE-1, REACTING SAID5-HYDROXY-8-METHOXY-TETRALONE-1 WITH METHYL MAGNESIUM IODIDE FOLLOWED BYHYDROLYSIS OF THE GRIGNARD INTERMEDIATE THUS OBTAINED TO FORM1-HYDROXY-4-METHOXY5-METHYL-7,8-DIHYDRONAPHTHALENE, REACTING THE LATTERCOMPOUND WITH OOSMIUM TETROXIDE IN ORGANIC SOLVENT SOLUTION ANDHYDROLYZING THE INTERMEDIATE OSMATE ESTER THUS FORMED TO PRODUCE1,5,6-TRIHYDROXY-4-METHOXY-5-METHYL-5,6,7,8TETRAHYDRONAPHTHALENE,HEATING THIS COMPOUND WITH AN AQUEOUS MINERAL ACID SOLUTION TO FORM5-HYDROXY-8METHOXY-1-METHYL-TETRALONE-2 WITHDIETHYLAMINODROXY-8-METHOXY-1METHYL-TETRALONE-2 WITHDIETHYLAMINOBUTANONE-2-METHIODIDE IN THE PRESENCE OF AN ALKALINECONDENSING AGENT.